An Expert Panel Discusses Immunotherapy and CLL

Published on
March 9, 2016

Topics include:
Treatment

Immunotherapy is personalized therapy for the
cancer patient. But can immunotherapy
outsmart CLL? From one of our CLL
Roundtables, Dr. John Gribben, Dr. Constantine Tam and Dr. William Wierda,
along with Patient Power Founder Andrew Schorr, discuss immunotherapy
advances. Listen as Dr. Tam reports that
he now tells his younger CLL patients, “We may well see the cure in your
lifetime.”

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educational grants from AbbVie and Genentech.

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Please remember the opinions expressed on Patient Power are not necessarily the views of our sponsors, contributors, partners or Patient Power. Our discussions are not a substitute for seeking medical advice or care from your own doctor. That’s how you’ll get care that’s most appropriate for you.

Andrew Schorr:

So let’s talk about where we’re headed. You’re gonna do different combinations, and
we’ll talk about people being in trials and the benefit to that. But when you develop cancer, your immune
systems let you down. There’s been a lot
of buzz about the immuno-oncology in solid tumors, etc. Can your immune system be helped, just like a
transplant helps it, and kind of a—if you can tolerate that—with these
checkpoint inhibitors that we’ve talked about in other illnesses to help fight
the cancer? Bill, do you want to comment on that

Dr.
Wierda:

Sure, and probably John is in a better position
to comment on that, because he’s generated a lot of the laboratory studies that
have been the basis for what we’re doing now in the clinic. I, several years ago, was looking at one of
these checkpoint inhibitors referred to as CTLA-4, and we found that there was
increased levels of CTLA-4 expressed in T cells of patients with CLL. CTLA-4 is a way that the immune system will
down-modulate the activation in T cells.
And so the T cells in patients with CLL have higher levels. And in the lab we showed that if you block
CTLA-4, you could reactivate T cells against patients’ own leukemia cells.

And so for a long time, I have intended to do clinical
trials in these antibodies. The original
antibody that was studied clinically was a drug that targeted CTLA-4 called
ipilimumab (Yervoy). It was very
difficult for us to get access to that for patients with CLL.

Nevertheless, it went forward, and there’s clinical activity
in solid tumors. We still haven’t been
able to test it in patients with CLL.
The toxicity is a little bit high.
It has a high side effect profile.
And there’s another checkpoint molecule that John can discuss I think
better than I can in terms of the laboratory investigations, but it’s referred
to as PD-1. It’s over expressed—or there
[are] high levels of expression of PD-1 also in T cells of patients with CLL. And there’s an antibody that targets PD-1
that appears to be a little bit better tolerated than the CTLA-4 antibody. So we’ve recently opened—and it’s called
nivolumab (Opdivo).

And it’s a Bristol Myers Squibb drug that they’ve gained
approval in solid tumors. So we have a
trial that just recently opened with nivolumab plus ibrutinib (Imbruvica) for
patients with CLL. I'm optimistic that
we’ll not only see activity in terms of treating the CLL but also some evidenceof immune reconstitution; fixing the
defects that patients have in their immune system that predisposes them to
develop infections and, perhaps, second cancers; skin cancers, etc.

Andrew
Schorr:

John, let me see if I understand this, and you
can add your perspective. So our immune
system let us down, if you will, and we started—the CLL cells proliferated. So this is the idea that we can help the
immune system do the job that it didn’t do that time.

Dr.
Gribben:

Sure, and it’s a little more complicated than
that. There are some cases where your
immune system fails, and you develop cancer.
It looks very much in CLL as if something else happens; you develop
CLL. And CLL is very effective at
switching off the immune system to be recognized. So it’s not like some lymphomas that come
from viruses in people whose immune system is suppressed. We’ve got very clear data that it’s the CLL
itself which is very immuno-suppressive.

Andrew
Schorr:

It’s like stealth. It has like a shield.

Dr.
Gribben:

Confoundedby the fact that treatments that we have like fludarabine (Fludara) really,
as well as killing off the CLL cell, killed off a lot of the immune
system. So we’ve spent a lot of time
trying to understand what was wrong with the immune system in CLL. We could see clearly by any measurement that
you did that T cells and K cells, B cells in individuals with CLL didn’t work
very well, as everyone with CLL knows in terms of the risk of increased
infections.

We did a lot of work trying to understand at the molecular
level why that happened and found out that one of the most important molecules
that did this is the PDL-1 molecule that is the one on the CLL cell that sticks
onto the PD-1 on the T cell that Bill’s got the clinical trials running on,
now. And so we had very clear evidence
in CLL this was an important molecule.
Actually, long before it was being developed in the solid tumors, the
issue was of course that the companies were much more interested in developing
it for the bigger markets.

But I think we had very, very strong evidence to suggest
that this was gonna be a really effective target here in this disease. And, of course, another huge advantage is the
toxicity profile looks pretty low. So
again, another whole arm you could add into the other types of treatments we’ve
been talking about.

Dr.
Wierda:

Just to add to what John’s saying, he mentioned
PDL-1. We also have a clinical trial
with another monoclonal antibody that’s directed against PDL-1, which is again
the molecule…

Andrew
Schorr:

So PD-1, PDL-1…

Dr.
Wierda:

Right.

Andrew
Schorr:

Okay.

Dr.
Wierda:

But the PDL-1 is on the CLL cells, and that’s how
they suppress the T cells.

Andrew
Schorr:

But all the ideas to help the immune system do
its job and help the CLL cell be recognized.

Dr.
Gribben:

What you’d really hope is that, as Con was
mentioning earlier, if you’ve got a cell that’s in there becoming resistant to
BTK inhibition, what you're really hoping at the same time is we can use
someone's own immune system as it recovers to go in and attack those
cells. So you’re looking to attack those
cells from every direction.

And really whatwe
want to get to—don’t get me wrong; it’s a great advance. We’ve got agents like ibrutinib and ABT-199
that you could go onto and take for the rest of your life. But I think what all of us are looking for is
you get rid of the last cell, and you stop the last treatment, and you’re off
it, and we’ve really cured the disease.
And at the speed with which things have been changing in this disease,
I'm really optimistic that we will get there.

Andrew
Schorr:

Really? So
the C word could be cure?

Dr.
Wierda:

Soon.

Dr.
Gribben:

Soon, yeah.

Andrew
Schorr:

Really?

Dr. Tam:

Yes, absolutely.

Andrew
Schorr:

So you hear that, folks? We’re talking about cure with this different
science coming together with more power; power to outsmart the CLL cell, which
has been…

Dr.
Gribben:

Pretty smart.

Andrew
Schorr:

...pretty smart.
Widely. Okay. So that means, then, can we hope that even if
we’re taking powerful medicines now, and they’re working pretty well. They’re
not without side effects. There’s no free lunch with powerful medicines. But many people do pretty well, or there’s
another medicine they can switch to, now, that may not have the same side
effect profile. But we all hope we can
be withoutmedicine and go on with
our life.

So are you saying—when you see patients, can you say I'm
working in the lab, and I'm also seeing patients, I can see that day
coming? You can?

Dr. Tam:

Yes, I do.
I think from our younger patients, what I tell them is you have a
disease that we conventionally think it’s incurable. We’ve got very good treatment for it, but we
conventionally think it’s incurable. But
the rate at which things are moving, we may well be seeing the cure in your
lifetime.

Andrew
Schorr:

Yeah, you’d be out of business, Con. You’re going to have to go and do something
else.

Dr. Tam:

I can always sell gelatti or something else.

Andrew
Schorr:

Okay. So
let’s talk about one other area that there’s been buzz about. And that is these CAR T cells, okay? Let me ask you first, Bill. So the idea was could you make a medicine
that, again, working on the immune system, had been expensive to make? There’s been some talk could there be sort of
an off-the-shelf approach where you add something from the patient, but you
have kind of a foundation, and it’s cheaper.

Where are we with that?
Is that still out there

Dr.
Wierda:

It’s still out there for a couple of
reasons. So for sure there’s activity in
using the CAR T cells directed against CD-19 to treat patients with CLL. There [have] been reports. The U-Penn group has reported excellent
outcomes and long-term remissions for patients who’ve received the—patients
with CLL who have received CAR T.
There’s toxicity associated with it, and it’s not insignificant
toxicity. So nearly a quarter of the
patients end up needing intensive care unit level care during their initial
portion of treatment.

For patients who are on ibrutinib or have all these oral
options, and they’re working and doing relatively well, that’s a hard pill to
swallow. So it’s gonna be initially a
treatment that we talk about with patients with very high-risk disease that
we’re very worried about or who may be failingand becoming resistant to these newer, more effective agents.

There’s been a lot of resources that have been directed at
developing the CAR Ts. There are
pharmaceutical companies that are involved now.
It’s very expensive. It’s a whole
new treatment. There isn’t really
anything that’s like it other than transplant.
And so it requires a lot of reagents that are new and different. It’s a personalized therapy. There are production facilities that they’ve
had to develop just to do the clinical trials.

And so that’s been a slow process, because it’s completely
new. It’s a completely new strategy. And
a lot of the infrastructure that’s been built has been built just to initiate
the clinical trials. And the initial
clinical trials have been written to treat ALL, which is a very aggressive type
of leukemia. ALL and diffuse large B
cell lymphoma. So these trials are now
opening.

We’ll be treating those patients with CAR Ts initially with
DLBCL or ALL. I think we’ll learn a lot
during that experience. It’ll become
safer; we’ll know how to better do it.
And then the time will come for CLL, and we’ll have that. It’s gonna be a year or two off, I think,
before there’s a significant number of trials that open for patients.

Please remember the opinions expressed on Patient Power are not necessarily the views of our sponsors, contributors, partners or Patient Power. Our discussions are not a substitute for seeking medical advice or care from your own doctor. That’s how you’ll get care that’s most appropriate for you.